Paliperidone palmitate: Japanese postmarketing mortality results in patients with schizophrenia

Abstract

Objective: Paliperidone palmitate once-monthly injectable (PP1M) is approved in Japan and other countries for the treatment of schizophrenia. During the 6 month Japanese early postmarketing phase vigilance (EPPV) period, 32 deaths were reported. This report reviews potential contributing factors to the fatal outcomes in the PP1M-treated population.

Research design and methods: All spontaneously reported adverse events following PP1M use received during EPPV from 19 November 2013 to 18 May 2014 were entered into the global safety database and these events were analyzed.

Results: During the EPPV period, 10,962 patients were estimated to have been treated with PP1M in Japan. The mortality reporting rate during this EPPV period was higher than that observed in the US or globally after PP1M launch (5.84, 0.43, and 0.38 per 1000 patient-years, respectively), but was consistent with the mortality incidence rates (10.2 per 1000 person-years) observed during interventional clinical studies in Japan and in observational patient cohorts. Of the 32 deaths reported during the Japanese PP1M EPPV period, 19/32 (59.4%) were in patients over 50 years of age, 23/32 (71.9%) reported cardiovascular risk factors and 25/32 (78.1%) received antipsychotic polypharmacy.

Conclusions: Based on this review of the 32 fatal cases in the PP1M EPPV period, the observed death rate does not necessarily result from a risk with PP1M treatment in Japanese patients. The higher mortality reporting rates in Japan may be attributed to a variety of factors: the effectiveness of mortality reporting in the unique Japanese EPPV program, the advanced age of the fatal cases, high cardiovascular risk factors, multiple underlying diseases and high antipsychotic polypharmacy among the cases with fatal outcomes.

Keywords:

• Early postmarketing phase vigilance
• Mortality
• Paliperidone palmitate
• Schizophrenia

Declaration of funding

The study presented in this report was sponsored by Janssen Research & Development LLC.

Author contributions: All the authors have contributed to the development and review of this article and are solely responsible for the opinions and research findings published in this article. Specific contributions – P.P.: design/conduct/data collection, data analysis and interpretation, development and review of the manuscript; S.G., D.H., and A.S. were the clinical team leaders and involved in data analysis; M.B.: is the pharmacovigilance scientist involved in design/conduct/data collection, data analysis and interpretation and review of the manuscript; M.M.: is the Global Medical Affairs leader and was involved with development and review of the manuscript; H.Q.: is the Global Epidemiology leader and involved in data analyses, interpretation, and review of the manuscript; T.H.: is the Japan development team leader and involved in data interpretation and review of the manuscript. A.F.: is the safety control manager and involved in data analysis and interpretation and review of this manuscript; M.T.: is the clinical scientist in Japan clinical team involved in interpretation, development and review of the manuscript; T.K.: as the Japan Medical Affairs leader was involved with development and review of the manuscript; Y.M.: is the pharmacovigilance scientist involved in data collection, data analysis and interpretation and review of the manuscript. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to publish these data and approved submission to this journal.

Declaration of financial/other relationships

P.P., S.G., A.S., H.Q., M.B., M.M., and D.H. have disclosed that they are employees of Janssen, R&D, USA. T.H., A.F., Y.M., and M.T., have disclosed that they are employees of Janssen R&D, Japan. T.K., has disclosed that he was an employee of Janssen R&D, Japan at the time of study; currently he is an employee of Johnson and Johnson Pte Ltd, Singapore.

CMRO Peer Reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Writing support was provided by Dr. Shirin Ghodke of SIRO Clinpharm Pvt. Ltd. and funded by Janssen R&D LLC, USA. We acknowledge Isaac Nuamah of Janssen R&D, USA for supporting statistical analysis and review.